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Dysregulation of TLR5 and TAM Ligands in the Alzheimer’s Brain as Contributors to Disease Progression

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Abstract

The hypothesis that accumulation of beta-amyloid (Aβ) species in the brain represents a major event in Alzheimer’s disease (AD) pathogenesis still prevails; nevertheless, an array of additional pathological processes contributes to clinical presentation and disease progression. We sought to identify novel targets for AD within genes related to amyloid precursor protein (APP) processing, innate immune responses, and the catecholamine system. Through a series of bioinformatics analyses, we identified TLR5 and other genes involved in toll-like receptor (TLR) signaling as potential AD targets. It is believed that Aβ species induce activation of microglia and astrocytes in AD, with a negative impact on disease progression. The TAM (Tyro3, Axl, Mer) family of receptor tyrosine kinases plays pivotal roles in limiting inflammatory responses upon TLR stimulation, for which we further studied their implication in the TLR5 alterations observed in AD. We validated the up-regulation of TLR5 in the frontal cortex of moderate AD cases. In addition, we observed up-regulation of the TAM ligands protein S (PROS1), galectin-3 (LGALS3), and Tulp-1. Furthermore, we identified an association of the TAM ligand GAS6 with AD progression. In THP-1 cells, co-stimulation with Aβ and flagellin for 24 h induced up-regulation of TYRO3 and GAS6, which could be prevented by neutralization of TLR5. Our results underscore the role of TLR dysregulations in AD, suggesting the presence of an immunosuppressive response during moderate disease stages, and implicate TAM signaling in AD immune dysregulation.

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Funding

Financial support for this study was obtained through the EU/EFPIA Innovative Medicines Initiative Joint Undertaking AETIONOMY (grant #115568) and the INMiND Project of the European Union to MTH.

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  1. Marisol Herrera-Rivero

    Present address: Department of Genomics, Life & Brain Research Center and Institute of Human Genetics, University of Bonn Medical School and University Hospital Bonn, Bonn, Germany

Authors and Affiliations

  1. Department of Neurodegenerative Disease and Gerontopsychiatry / Neurology, University of Bonn Medical Center, Sigmund-Freud-Str. 25, 53127, Bonn, Germany

    Marisol Herrera-Rivero, Markus P. Kummer & Michael T. Heneka

  2. German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

    Francesco Santarelli, Frederic Brosseron & Michael T. Heneka

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  1. Marisol Herrera-Rivero
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  4. Markus P. Kummer
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  5. Michael T. Heneka
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Contributions

MHR: Conceived and designed the study, performed the bioinformatics analyses and lab experiments, analyzed and interpreted the data, and prepared the manuscript.

FS: Performed the cell culture experiments.

FB: Helped with the design of cell culture experiments.

MPK: Provided support and advice for the cell culture experiments, and contributed with critical revisions to the manuscript.

MTH: Conceived and designed the study, helped with manuscript preparation, and approved the final version of the manuscript.

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Correspondence to Michael T. Heneka.

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Herrera-Rivero, M., Santarelli, F., Brosseron, F. et al. Dysregulation of TLR5 and TAM Ligands in the Alzheimer’s Brain as Contributors to Disease Progression. Mol Neurobiol 56, 6539–6550 (2019). https://doi.org/10.1007/s12035-019-1540-3

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